tbuckley/cabot-search huggingface dataset:
QOL-01. VARIABILITY IN ANXIETY AND DEPRESSION SYMPTOMS AFTER ELOQUENT GLIOMA RESECTION IS ASSOCIATED WITH CHANGES IN FUNCTIONAL CONNECTOMIC PROPERTIES
Authors: Kyle Noll, Henry Chen, Mariana Bradshaw, Jeffrey Wefel, Catherine Sullaway, Ashley Thomas, Vinodh Kumar, Sujit Prabhu, Ho-Ling Liu
Journal: Neuro-Oncology (2023)

Abstract Little is known regarding how treatment-related changes in cerebral networks relate to symptoms of anxiety and depression in patients with glioma. Fifteen patients with left perisylvian glioma underwent resting-state fMRI and neuropsychological evaluation before and 1 month after resection. Symptoms of depression and anxiety were characterized with Beck Depression Inventory-II (BDI) and Beck Anxiety Inventory (BAI) Total scores and rates of clinically significant symptom burden. Change scores and reliable change classifications were also examined. Graph theoretical analysis was applied to fMRI connectivity matrices to calculate brain network properties. Comparison of pre- and postoperative measures were performed with Wilcoxon tests. Correlations between changes in anxiety and depression symptom measures and network properties were examined. Pre- and postoperative Total scores did not significantly differ though postoperative symptom burden trended toward reduction [Change: BDI=-1.93(5.73), BAI=-5.80(8.19)] with considerable interindividual variability noted [Change: BDI range=-12 to +6; BAI range=-18 to +6]. Preoperatively, at least mild symptoms were found in 27% of patients on BDI and 60% on BAI. Postoperatively, rates were the same for BDI while BAI was 33%. Using reliable change criteria, improvement was found in 13% of patients on BDI and 33% on BAI without any significant worsening. Significant postoperative connectivity decreases were observed in betweenness centrality [Change = -5.56(12.07), p = .031] and assortativity [Change=-.062(.096), p = .027]. Strong associations were found between pre- to postoperative differences in betweenness centrality and assortativity and changes in BDI [ρ(13)=.58 and .67, p&amp;lt; .02] and BAI Total scores [ρ(13)=.62 and .68, p&amp;lt; .01]. Anxiety and depression symptoms vary considerably postoperatively, though most patients do not show significant worsening. Variability in symptom change appears related to alterations in functional connectomics, with those showing increases in certain connectomic properties exhibiting worse postoperative anxiety and depression symptoms. Surgically-induced connectomic changes may coincide with or potentially contribute to psychological symptom differences in the postoperative setting.
QLTI-11. TIMELINE FROM INITIAL MRI TO INTERVENTION IN NEWLY DIAGNOSED HIGH GRADE GLIOMA
Authors: Colby Cevering, Maninder Kaur
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVE Prompt treatment of high-grade glioma is crucial for prolonging life. In an attempt to identify factors that lead to delays in treatment, we evaluated the amount of time between initial MRI and treatment start date for our patients with newly diagnosed high grade glioma. METHODS This was a retrospective chart review study. Adults over the age of 18 years of age with newly diagnosed high grade glioma were included if they were seen by the neuro-oncology department at Loma Linda University Medical Center. Reviewed charts were dated from November 2020 to August 2022. We evaluated the amount of time between initial MRI and several important milestones in the diagnosis and treatment of high grade glioma, including resection; biopsy results; neuro-oncology consult; radiation-oncology consult; date that chemotherapy was ordered, received by the patient, and initiated; and radiation therapy start date. RESULTS Twenty-two patients with new diagnosis of high-grade glioma were identified. Six patients were excluded due to complicated treatment courses involving outside facilities. Sixteen patients were included in the study. Thirteen patients (81%) had a diagnosis of glioblastoma, 2 (12%) had a diagnosis of diffuse midline glioma, and 1 (6%) had a diagnosis of anaplastic astrocytoma. The mean number of days between initial MRI and chemotherapy start date was 88. Prolonged timelines were seen in all analyzed metrics. CONCLUSIONS There is a significant delay in chemotherapy initiation for patients with high grade glioma at our facility. We also provide a framework for other institutions to evaluate their system processes in order to improve care delivery.
EXTH-67. LP-184, AN MGMT-AGNOSTIC SMALL MOLECULE, HAS POTENT SYNERGY WITH SPIRONOLACTONE TO EFFECTIVELY INHIBIT ORTHOTOPIC GBM XENOGRAFT TUMORS
Authors: Bachchu Lal, Aditya Kulkarni, Joseph McDermott, Hernando Lopez-Bertoni, Kishor Bhatia, Panna Sharma, John Laterra
Journal: Neuro-Oncology (2023)

Abstract Temozolomide (TMZ) is currently the most effective standard-of-care chemotherapy based on its ability to extend survival of patients with newly diagnosed MGMT-methylated glioblastoma (GBM). Blood-brain barrier (BBB) permeable agents effective against TMZ-resistant GBMs (i.e. recurrent GBM, MGMT-unmethylated GBM) are needed. Lantern Pharma is advancing LP-184, an acylfulvene prodrug activated by the enzyme PTGR1. In MGMT-expressing TMZ-resistant GBM cultures, LP-184 was found to be ~5000X more potent than TMZ with LP-184 IC50s ranging from 20-200 nM. DNA damage induced by acylfulvenes is primarily repaired via transcription-coupled nucleotide excision repair (TC-NER) mediated by ERCC complexes. ERCC3 is proteolytically degraded in response to the FDA approved BBB permeable diuretic, spironolactone (SP). We found that SP induces rapid ERCC3 degradation by up to 95% in GBM cells and validated that SP-induced ERCC3 loss led to substantial increases in LP-184 responses (DNA damage, tumor cell death) in vitro and in subcutaneous (s.c.) tumor xenografts. Co-treatment of GBM cells with LP-184 and SP resulted in a 3-6 fold decrease in LP-184 IC50s in PDX-derived (M1123 and Mayo39) and cell line (U87) cultures in vitro. Systemic SP sensitized pre-established s.c. and orthotopic (i.c.) GBM xenografts to LP-184 therapy. Pre-established s.c. U87 tumors recurred after initial regression in 5/5 animals following treatment with LP-184 alone whereas tumors showed durable complete regression without recurrence in 4/5 animals following treatment with LP-184 + SP. Pre-established M1123 i.c. xenografts treated with LP-184 + SP were ~3-fold smaller than those treated with LP-184 alone. LP-184 is a promising agent with potential clinical translation in GBM patients. Our results indicate that LP-184 is MGMT-agnostic and effective in TMZ-resistant preclinical GBM models. The first-in-human LP-184 dose escalation Phase 1A trial enrolling solid tumor patients including GBM is planned to launch Q3 2023.
IMMU-57. EFFECT OF THE ONCOMETABOLITE D2HG ON MYELOID-DERIVED SUPPRESSOR CELL POPULATIONS
Authors: Oriana Teran Pumar, Maria Figueroa, Defne Bayik
Journal: Neuro-Oncology (2023)

Abstract Mutations in the isocitrate dehydrogenase 1/2 (IDH1/2) enzyme correlate with better prognosis of gliomas, partly due to enhanced infiltration of nonimmunosuppressive granulocytic cells compared to IDH wild-type (IDHwt) tumors. Altered cytokine/chemokine secretion from tumor cells and reprogramming of myeloid cell metabolism are among the factors that drive differences in immune profiles of IDHwt vs. IDHmut tumors. IDH mutant protein produces the oncometabolite D-2-hydroxyglutarate (D2HG) instead of the canonical alpha-ketoglutarate (αKG), a co-factor for histone and DNA demethylases. Since D2HG is known to be secreted into the tumor microenvironment (TME), we interrogated the effect of this metabolite on the epigenetic landscape and behavior of granulocytic and monocytic myeloid-derived suppressor cells (g/mMDSCs). Co-culturing bone marrow cells with either IDHmut or IDHwt glioma cells demonstrated that mMDSCs, which we previously showed to be the abundant tumor infiltrating MDSC subtype in IDHwt tumors, but not gMDSCs specifically experience higher levels of apoptosis when exposed to IDHmut cells. Treatment of bone marrow cells with physiologically relevant concentrations of either D2HG or αKG demonstrated that D2HG re-capitulates the pro-apoptotic effect on mMDSCs. Furthermore, co-cultures of IDHmut glioma cells and bone-marrow cells induced a pronounced increase in global methylation on mMDSCs specifically, and we observed that mMDSCs and gMDSCs differentially express histone demethylases via western blotting. Collectively, these results suggest that D2HG can differentially impact mMDSC vs gMDSC biology by epigenetic reprogramming. Future studies will elucidate the specific targets of D2HG in mMDSCs that renders these cells more susceptible to apoptosis with the goal of identifying the mechanisms that can be modulated to down-regulate mMDSC infiltration and/or survival within the TME.
EXTH-17. TARGETING CTPS1 AND NUCLEOTIDE BIOSYNTHESIS PATHWAYS AS A NOVEL THERAPEUTIC APPROACH IN MYC-AMPLIFIED MEDULLOBLASTOMA
Authors: Matthew Hathaway, Hawa Jagana, Michael Meechan, Ashmitha Rajendran, Barbara Slusher, Myron Evans II
Journal: Neuro-Oncology (2023)

Abstract MYC-amplified medulloblastoma (MB) tumors are the deadliest of all subgroups with a &amp;lt; 50% 5-year overall survival rate. High risk patients receive large doses of chemo- and radio- therapy (CT/RT) with most survivors experiencing debilitating neurological and cognitive sequelae making the identification of novel targets of the utmost importance. Recent whole-genome CRISPR screening identified the enzyme CTPS1 and other components of the de novo pyrimidine metabolism cascade as a possible cancer-specific vulnerability in MYC-amplified MB. Our study tested targeted inhibitors of this pathway to identify rational combinations for translation to pre-clinical models. A stable of treatment-naïve, patient-derived models of MYC-amplified MB were used and treated with various de novo pyrimidine synthesis inhibitors alone and in novel combinations. Analysis of proliferation, cell survival, and downstream signaling were performed both in vitro and in vivo. Inhibition of CTPS1 led to a significant decrease in cell proliferation and alterations in cell cycle with minimal increases in cell death, suggest a cytostatic mechanism. Previous work has shown de novo pathway inhibition results in reduction of the dNTP pool, leading to activation of the DNA damage response (DDR), seizing the cell cycle. Interestingly, the DDR inhibitor prexasertib (CHKi) robustly targets MYC-amplified MB tumors in pre-clinical models. Combining CHKi and CTPS1 inhibitors yields significant tumor cytotoxicity both in vitro and in vivo. We further demonstrated robust synergy of CHKi with other clinically relevant de novo pyrimidine metabolism inhibitors. The results of this investigation confirm CTPS1 and the de novo pyrimidine metabolism pathway as targets in MYC-amplified MB and identifies a novel rational combination for treatment in patients.
DISP-15. DISPARITIES IN THE AVAILABILITY OF NEURO-ONCOLOGY CLINICAL TRIAL SUPPORTING INFRASTRUCTURE IN THE UNITED STATES
Authors: Yeonju Kim, Terri Armstrong, Mark Gilbert, Orieta Celiku
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Barriers to clinical trial access have significant implications for patient care and disproportionally impact rural and socioeconomically disadvantaged populations. Expanding on reported disparities in neuro-oncology trial availability, we assessed whether existing networks of clinical providers and collaboratives, including NCI’s National Clinical Trials Network (NCTN) and Community Oncology Research Program (NCORP), can effectively bridge these disparities. METHODS Locations of adult neuro-oncology trial sites, UCNS-certified neuro-oncologists, NCTN Main Members, NCORP Community Affiliates, and general oncologists reporting to Centers for Medicare/Medicaid Services were obtained, mapped to zip code tabulation areas (ZCTAs), and annotated with US Census population and geography data and the Neighborhood Atlas Area Deprivation Index (ADI). Regression and spatial analyses were conducted assessing the role of geography, socioeconomic disadvantage, and population on infrastructure accessibility. RESULTS We identified 1976 neuro-oncology trials, 586 NCTN institutions, 962 NCORP sites, 306 neuro-oncologists, and 863 general oncologists located in just 8% of all ZCTAs, inhabited by 19% of the US population. All trial-supporting infrastructure components were more likely to exist in more populated, geographically neighboring regions (OR &amp;gt;1, p&amp;lt; 0.00001). Trial sites, NCTN institutions, and neuro-oncologists served ZCTAs with less disadvantage (OR=0.99, p=0.03958; OR=0.99, p&amp;lt; 0.00001; OR=0.98, p&amp;lt; 0.00001), while NCORP served more disadvantaged areas (OR=1.01, p=0.00102) and general oncologists were distributed similarly across ADI (OR=1.00, p=0.94317). Investigating potentially underutilized infrastructure, 2 neuro-oncologists, 8 NCTN institutions, 10 NCORP sites, and 107 general oncologists were located more than 25 miles from utilized trial sites. CONCLUSION The identified disparities in neuro-oncologists and trial-supporting institutions reflect disparities in trial-site access and point to broader disparities in neuro-oncology care access. NCORP sites reach more socioeconomically disadvantaged populations, but the overall sparsity of trial-supporting networks indicates that the existing infrastructure cannot effectively bridge trial-access barriers and novel approaches including telehealth and decentralized trial designs may be necessary to promote equity.
CTNI-29. A PHASE 2 STUDY TO EVALUATE EFFICACY AND SAFETY OF ACT001 AND TEMOZOLOMIDE COMBINATION TREATMENT IN PATIENTS WITH RECURRENT GLIOBLASTOMA MULTIFORME
Authors: Wenbin Li, Qun Li, Liang Wang, Dongpo Cai, Xunjun Yang
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Han Chinese patients with rGBM were randomly assigned to one of three cohorts in this phase 2 open label study: Arm A (ACT001, 400mg, BID), B (ACT001 and temozolomide combination) and C (TMZ or CCNU). Study endpoints include 1-year OS rate, PFS (by iRANO) and AE incidence. RESULTS 7, 6 and 6 patients were enrolled to Arms A, B and C respectively including one patient in Arm C with a mutant IDH1 (R132H). The median age was 52 years (range: 34-68) and male to female ratio 11/8. In addition to 7 SAEs, 189 TEAEs were reported in this interim analysis including 49 and 70 chemo-related AEs in Arm B and Arm C. Post enrollment MRI scans were performed in 6,6 and 4 patients in Arms A, B and C respectively. Despite the lack of objective response and difference in 1-year OS, a prolonged PFS lasting at least 12 months was noted in 3 patients including the patient with mutant IDH1 in Arm C (23 months and ongoing) and two patients in Cohort B (19 and 22 months, both ongoing) who were sensitive to TMZ in first line treatment as shown by at least 12-month interval between TMZ initiation and first relapse. Among 18 patients with wild type IDH, the prolonged stable disease was restricted to combination Arm whereas either the four patients with positive MGMT methylation or two patients with a similar history of sensitivity to first line TMZ treatment didn’t have such prolonged stable disease after being treated with TMZ or ACT001 alone during this study. CONCLUSIONS ACT001 restored sensitization of rGBM patients to TMZ treatment in sub-group of patients likely due to reduced DNA repair capacity by ACT001 treatment. Further study is warranted to evaluate the effect of ACT001 and TMZ combination in phase 2b study.
TMIC-61. INVESTIGATING REPROGRAMING OF THE GBM’S TUMOR MICROENVIRONMENT AS A RESULT OF CO-TRANSFER OF HEMATOPOIETIC STEM CELLS (HSCS) WITH ADOPTIVE CELLULAR THERAPY
Authors: Alexandra Reid, Dan Jin, Bayli DiVita Dean, Laura Falceto Font, Connor Francis, John Figg, Catherine Flores
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is an incredibly aggressive and prevalent primary CNS tumor with dismal survival outcomes. GBM’s intra-tumor heterogeneity and the powerful regulatory mechanisms within the tumor microenvironment (TME) that hamper immune activation have proved to be formidable challenges to the development of effective therapies. Fortunately, immunotherapy has emerged as a potentially powerful approach to achieve of immune activation within the TME through adoptive immunotherapy and checkpoint inhibition Our previous work has demonstrated that the survival benefit of adoptive cellular therapy (ACT) is significantly enhanced by concomitant transfer of bone marrow derived hematopoietic stem cells (HSC) with tumor-reactive T cells in preclinical models. Using a novel organotypic brain slice culture (BSC) model study using glioma-bearing C57BL/6J mice, we interrogate tumor microenvironment and directly demonstrate that the presence of HSC-derived cells in the microenvironment increases T cell migration to tumor, and increased tumor cell death. In addition, we can investigate reprogramming of the TME as a result of treatment with this ACT+HSC platform. These studies are unique in that through this model system, we are capable of studying the cell-cell interactions occurring within the tumor microenvironment TME longitudinally while accounting for the complexity and the spatial orientation of the components within the TME that promote immunosuppression and tumor escape.
EPID-31. BRAIN TUMORS IN UNITED STATES MILITARY VETERANS
Authors: Kristin Waite, John Bihn, Gino Cioffi, Corey Neff, Carol Kruchko, Quinn Ostrom, Kaitlin Swinnerton, Danne Elbers, Michael A Mooney, Jacob Rachlin, Thor Stein, Mary Brophy, Nhan Do, David Priemer, Daniel Perl, Ryan Ferguson, Richard Hickman, Burt Nabors, Jennifer Rusiecki, Jill Barnholtz-Sloan, Nathanael Fillmore
Journal: Neuro-Oncology (2023)

Abstract Veterans account for ~7% of the adult United States population, with half seeking care through the Veterans Health Administration (VHA). A comprehensive analysis of incidence and survival for brain tumors in the Veteran population has been lacking. Veteran data was obtained from VHA Medical Centers that diagnose and treat cancer via the VHA Corporate Data Warehouse. Brain tumor statistics on the overall US population were generated from the Central Brain Tumor Registry of the United States data. Cases were defined as individuals (≥18 years) with a primary brain tumor, diagnosed between 2004-2018, and identified using administrative criteria based on International Classification of Diseases for Oncology, Third Edition (ICD-O-3) topography and morphology codes. Annual age-adjusted incidence rates (AAIR) and 95% confidence intervals were estimated per 100,000 population. Kaplan-Meier survival curves were generated to evaluate overall survival outcomes among Veterans. The Veteran population was primarily white (78%), male (93%), and between 60-64 years old (18%). Individuals with a primary brain tumor in the general US population were mainly female (59%) and between 18-49 years old (28%). The overall AAIR of primary brain tumors from 2004-2018 within the VA cancer registry was 11.6. Non-malignant tumors were more common than malignant tumors (AAIR:7.19 vs 4.42). The most diagnosed tumors in Veterans were non-malignant pituitary tumors (AAIR:2.96), non-malignant meningioma (AAIR:2.62), and glioblastoma (AAIR:1.96). In general, in the Veteran population, survival outcomes became worse with age and were lowest among individuals diagnosed with glioblastoma. Differences between the Veteran and US population can be broadly attributed to the differences in the demographic composition of these groups. Prior to this study, there have been no reports on national level incidence rates and survival outcomes for Veterans. Statistics like these provide vital information that drive efforts to understand disease burden and improve outcomes for individuals with primary brain tumors.
CNSC-43. TARGETING NEURONAL EXCITABILITY FOR <i>NF1</i> LOW-GRADE GLIOMA THERAPY
Authors: Corina Anastasaki, Jit Chatterjee, Yunqing Gao, Joshua P Koleske, Stephanie L Bozeman, Ji-Kang Chen, Chloe M Kernan, David Gutmann
Journal: Neuro-Oncology (2023)

Abstract While neuronal activity has previously been implicated in malignant glioma growth control, we recently demonstrated that neuron excitability can also regulate low-grade (optic) glioma initiation and progression. In this prior study, we showed that NF1 germline mutation-dependent neuronal excitability sustains optic glioma growth through HCN channel-mediated midkine activation of a T cell-microglia stromal circuit. Relevant to clinical translation, lamotrigine modulation of HCN channel function reduced neuronal hyperexcitability, midkine production and optic glioma (OPG) growth. To establish an obligate role for neuronal activity and midkine (Mdk) production in OPG growth, we leveraged a series of unique genetically engineered mouse models. First, we demonstrate that midkine is necessary for gliomagenesis, as Nf1-OPG; Mdk-/- mice do not develop tumors and have restored retinal pathology, as evidenced by increased retinal ganglion cell (RGC) numbers and retinal nerve fiber layer thickness. Second, we show that midkine production and neuronal hyperactivity are interdependent, such that only tumor-associated germline Nf1 mutations result in increased RGC excitability and midkine production, whereas those mutations that do not cause optic gliomas lack RGC hyperexcitability or elevated midkine expression. Third, lamotrigine treatment both during and after Nf1-OPG development attenuates midkine levels and tumor proliferation. Moreover, this anti-tumoral effect is durable for months after the cessation of treatment. Fourth, oral treatment of Nf1-OPG-bearing mice with clinically relevant doses of lamotrigine (2.5-7.5mg/kg/day) during OPG development blocks tumor formation. Together, these data establish midkine and neuronal hyperexcitability as key drivers of Nf1 optic glioma growth, relevant to planned clinical trials of this anti-seizure medication for children with NF1-OPG.